Environmental influences on epilepsy gene mapping in EL mice

The epileptic EL mouse has been studied extensively as a genetic model for idiopathic complex partial seizures in humans. The seizures in EL mice occur during routine handling at approximately 90 days of age, but can be induced at younger ages (50 days) by repeated rhythmic vestibular stimulation, e.g., tossing. Six seizure frequency quantitative trait loci (QTLs), El1-El6, were previously mapped in crosses between EL and non-epileptic strains using mechanical tossing procedures beginning at 30 days of age. The presence of these seizure frequency QTLs depended upon genetic background and the type of cross. Here we confirm Chromosome 2 and 9 QTLs in a backcross to the seizure-resistant ABP/LeJ strain with mice tested beginning at 200 days of age. However, the mapping of epilepsy genes was influenced by the seizure testing procedure, i.e., repeated tossing. The maximum Z-score for El1 (Chromosome 9) was 3.7 after 6 tests, but decreased to 2.4 after 15 tests. In contrast, the maximum Z-score for El2 (Chromosome 2) was 2.0 after 6 tests, but increased to 3.9 after 15 tests. In addition to nonallelic interactions (epistasis), our findings indicate that the genetic complexity of tossing-induced seizure susceptibility in EL mice also arises from genotype-environmental interactions involving the seizure test, seizure history, and age.